Up to one third of the 700,000 men and women who served in Operations Desert Shield and Desert Storm during the 1990-1991 Gulf War (GW) have developed a chronic multisystem illness known as Gulf War Veterans' Illness (GWVI). Neurobehavioral findings include memory problems, executive system deficits, slowed motor and processing speeds, sustained attention deficits, reduced visuospatial skills and psychomotor dysfunction. Given the spectrum of cognitive deficits noted above, combined with evidence of structural and functional abnormalities on neuroimaging, it is likely that neuropathological changes also occur in GWVI. Several environmental exposures have been implicated as potential contributors to GWVI including exposure to acetylcholinesterase (AChE) inhibitors such as pyridostigmine bromide (PB; anti-nerve gas pills) and organophosphate (OP) pesticides/nerve agents (e.g., sarin/cyclosarin). The pattern of deficits may be related to whether GWV were exposed to OP nerve agents as well as their premorbid vulnerability (e.g., PON1 status) to such exposures. GWV may also be at higher risk for developing a progressive neurodegenerative disorder such as Alzheimer's Disease as they age. Some studies suggest that accelerated aging may occur in GWVI related to axonal transport deficits, increased axial diffusivity, increased WM anisotropy on diffusion tensor imaging and insulin resistance and/or metabolic syndrome. Findings of reduced hippocampal volume in GWV suggest that that the pattern of deficits may be consistent the development of an Alzheimer-type dementia. This is important to investigate because the GWV cohort in general is aging; 52% of GWV are age 45 and older and 16% are age 55 to 85+. In addition, recent evidence suggests that an unexpectedly large number of GW veterans sustained traumatic brain injuries (TBI) so they may also be at risk for long term sequelae such as chronic traumatic encephalopathy (CTE). Given the issues raised above, there is a critical need for a GWVI CNS tissue biorepository that will conduct extensive ante mortem longitudinal assessments on enrolled GWV. Our first specific aim is to establish a VA GWVIB as a national resource to support research on the etiology and pathogenesis of GWRI and our second aim is to perform selected psychometric and biological assessments on enrollees to maximize the value of tissue donated to the GWVIB. Well-characterized CNS tissue when combined with antemortem health data and biological assessments (such as ApoE genotype and serum PON1 activity) will be invaluable to advance research on GWVI. The GWVIB will be a multi-site collaboration among VA Boston Healthcare System (VABHS) and the Southern Arizona VA Healthcare System (SAVAHCS). The GWVIB will utilize strengths across the Boston and Tucson sites in enrollment, tissue collection, processing, storage, neuropathological diagnosis, medical informatics and data management. VABHS will serve as the operations/data coordinating center and conduct the neuropathological diagnostic analyses, with SAVAHCS contributing expertise in CNS tissue processing and storage. SAVAHCS will also coordinate CNS tissue distribution. Notable enhancements to be initiated are the utilization of an active versus passive recruitment approach, enlarging our collection of tissue from Veteran controls through a collaboration with the National Disease Research Interchange (NDRI), and improved outreach to investigators to increase the utilization of the GWVIB in GWI research. This will allow us to leverage the substantial investment of VA resources already in place at GWVIB and to add value to existing clinical and CNS tissue resources.